The overall goal of this project is to advance the discovery and development of novel inhibitors of the system xc- glutamate/cystine antiporter (Sxc-), specifically targeting a newly identified allosteric site on the transporter. Sxc- is an obligate exchanger that links the import of L-cystine (L-Cys2) with the export of L-glutamate (L-Glu). Sxc- function is particularly critical in the CNS, as it mediates the uptake of a vital sulfu-containing amino acid needed for glutathione (GSH) synthesis and oxidative protection, while simultaneously producing an efflux of an excitatory neurotransmitter well known for its contributions to fast and slow synaptic signaling, synaptic plasticity and excitotoxic pathology. Emerging evidence also indicates that changes in SxC- activity are associated with the underlying pathological mechanisms of a variety of CNS disorders, the most prominent of which are glial brain tumors and drug addiction/relapse. Unfortunately, our growing appreciation for the functional significance of Sxc- in the CNS has rapidly outpaced the availability of potent and selective small molecules with which to modulate transporter activity. Recent synthetic and SAR-based pharmacological studies in our group have identified a novel series of potent noncompetitive inhibitors of Sxc- that we hypothesize are interacting with at least two distinct lipophilic domains adjacent to the substrate binding site on the transporter. Our identification of this new class of noncompetitive inhibitors and, consequently, a previously unrecognized binding site that can allosterically modulate transporter activity, provides an entirely new opportunity for inhibitor development. Using iterative cycles of synthesis and pharmacological assessment, linked by pharmacophore modeling, we propose to build on our lead compounds and optimize the potency and specificity of these Sxc- inhibitors. The proposed synthetic and pharmacological studies address a significant unmet need in the development of small molecules with which to probe the function of Sxc-, as well as its potential as a therapeutic target.